Pain is the major patient complaint with systemic illness, traumatic injuries and surgery. The last decade has resulted in new knowledge that is leading to significant improvements in the management of persistent pain. Nevertheless, important gaps in our understanding remain. Many difficult to treat persistent pains involve deep visceral and muscle tissue. Research on the development of nociceptive systems is minimal as the effect of early infant persistent injury is limited above the level of the brain stem, yet multiple forebrain structures participate in the perception of pain. The major theme of this program project is the study of modulatory influences in nociceptive circuitry in response to persistent visceral and cutaneous tissue injury and the effect of neonatal exposure to pain on such plasticity. The individual projects all take advantage of the development of new animal models of inflammation and examine the changes that take place in primary afferent neurons, dorsal horn circuitry and descending modulatory pathways in adults after injury and the impact of neonatal injury on these changes. Project #1 will study the changes in dorsal horn excitability that take place after cholonic inflammation in the rat and how descending modulatory mechanisms contribute to the sensitization process. Project #2 will focus on the role of early postnatal pain experience as a risk factor for the development of nociceptive systems and the neurochemical reorganization of dorsal root ganglia neurons and spinal dorsal horn neurons. Project #3 will study the modulation of primary afferent excitability and their underlying biophysical properties after inflammation in the adult and the effect of neonatal injury on these changes. Project #4 will examine the influence of forebrain structures on descending modulatory effects in a rat model of cutaneous inflammation and the effects of neonatal cutaneous and visceral pain experience on these descending circuits. Project #5 will use a model of inflammatory hyperalgesia systems in these effects, and the neuroprotective role of gustatory stimulation in preventing developmental changes in nociceptive circuitry produced by neonatal injury. In summary, this program project grant brings together a group of experts in the field of pain to study the role of neuronal modulation in animal models of persistent pain.